Cigarette smoking has been recognized as a major public health problem for more than ten years. Despite a high degree of public awareness of this fact, the proportion of smokers has decreased but slightly in the past ten to fifteen years. A 1975 survey sponsored by the United States Department of Health, Education and Welfare reported that 39.3% of adult males and 28.9% of adult females in this country were current smokers, averaging 23 cigarettes a day and 19 cigarettes a day, respectively. (Adult Use of Tobacco--1975, United States Public Health Service, 1976.) The extraordinary persistence of the smoking habit is further highlighted by the high degree of awareness among smokers of the health hazard. Two-thirds of the smokers surveyed were concerned about possible effects of cigarette smoking on their own health.
Despite the high level of awareness of health hazard, the smoking habit remains extraordinarily persistent and difficult to break. The above cited survey reported that 61% of current smokers had made at least one serious attempt to quit smoking. A full 90% of current smokers had either tried to quit smoking or would probably do so if there were an easy way to stop.
The smoking habit is perceived as being difficult to break. Recidivism is high. Yet, it is clear that there is both a need and a demand of long standing for a convenient and relatively easy method for aiding smokers in reducing or eliminating cigarette consumption.
The smoking habit is maintained and reinforced by a combination of social, psychological and physiological responses whose nature and relative importance and interactions remain poorly understood. The rate of consumption among smokers commonly fluctuates in response to worry, stress and anxiety. In addition, physiological adaptations to the pharmacological actions of nicotine cause sensations of discomfort and/or unease when the smoker attempts to quite smoking. Although the dynamics of the interaction of the pharmacological, physiological and psychological factors contributing to the smoking habit are as yet poorly understood, it is well known that the habit is difficult to break. Prior art methods for stopping or reducing smoking include the exercise of will power, various psychological conditioning techniques, and the administration of various substances designed to counteract or substitute the supposed habituating effects of nicotine.
A comprehensive survey of prior art methods for reducing smoking behavior is Larson, P.S. and Silvette, H., Tobacco Experimental and Clinical Studies, Supplement 2, The Williams and Wilkins Company, Baltimore, 1971. The exercise of will power, or simply quitting smoking without the use of any aids, substitutes or other devices, remains at least as successful as any other method. A related method is that of tapering off, involving a gradual reduction in number of cigarettes smoked over a period of time. The method is less reliable because much smoking behavior is unconscious and success requires very close monitoring of the actual number of cigarettes smoked. Various commercial devices, such as filters of graded capacity, have been marketed as aids to the tapering off method.
A variety of techniques have been advanced involving some sort of aversion conditioning. One approach is to provide the smoker with a substance which creates a bad taste in the mouth or interacts with the cigarette smoke to produce unpleasant sensations in the mouth. For example, mouth washes and lozenges containing silver nitrate, silver acetate and/or copper sulfate have long been recommended, either alone or in combination with psychoactive drugs or psychotherapy. Similarly, vegetable bitters such as tulip poplar bark, quassia and ginseng root have been stated to render the tobacco taste unpleasant. The effectiveness of such methods is considered to be questionable. A major disadvantage of such self-administered aversion treatments is the east of discontinuing the course of treatment. Some success has been achieved in an in-patent setting with other forms of aversion therapy, such as psychotherapy coupled with administration of electric shocks. However, these methods are expensive, as well as time consuming, and if the patient reacquires the habit, he or she will be less likely to submit to the therapy a second time.
Other forms of treatment are based upon the supposed habituating effects of nicotine. One approach in the prior art has been to disassociate the mechanical and sensory aspects of the smoking habit from the pharmocological effects of nicotine by providing for the administration of a maintenance dose of nicotine while removing or discontinuing the use of cigarettes. A chewing gum containing nicotine has been developed and tested with apparent success (Brantmark, B., et al, Psychoparmacologia Berl.) 31, 191 (1973); (Ferno, O., et al., Psychopharmacologia, Berl.) 31, 201 (1973). A difficulty with the method is that a physiological dependence upon nicotine remains and until such dependence is overcome, the opportunity to resume smoking at the original pretreatment dose level is very high. In addition, the method fails to solve the long term health problems presented by nicotine administration.
A substantial amount of research and commercial activity has been associated with the use of lobeline. The pharmocological action of lobeline is described as a weak nicotine-like action, but devoid of the pleasurable sensations of nicotine and apparently discontinuable without a withdrawal syndrome. Therefore, the use of lobeline for tobacco dishabituation is based upon a plausible substitution hypothesis. In addition, lobeline has an extremely bitter taste and when administered in combination with nicotine produces highly disagreeable symptoms. Consequently, there is an element of aversion conditioning in lobeline therapy systems. Lobeline may be administered by intramuscular or subcutaneous injection, or perorally, in tablets, chewing gums, lozenges and the like. However, when studied in controlled double blind tests against placebo, lobeline has been found to be ineffective, i.e., no more effective than placebos (Merry, J. and Preston, G., The Practitioner (May, 1963), pp. 629-631).
The results with lobeline point up two procedural difficulties in experimental design of any test of a method or product for reducing smoking behavior. First, there is in all studies a large placebo effect for any agent which is administered. The dynamics of this placebo effect are not known. However, the placebo effect alone may result in a decrease of as much as 50% in the amount and frequency of cigarettes smoked. Second, the psychological state of patients who enter treatment or experimental studies of an anti-smoking treatment must be taken into account. For example, a smoker who expresses a desire to quit but says he cannot do so on his own, may, in fact, be subconsciously committed to continued smoking, or may be satisfied with a reduction of 50%. Consequently, the circumstances under which test subjects are chosen must be considered with care.
The compounds 3-hydroxy-2-methyl-4-pyrone (maltol) and 3-hydroxy-2-ethyl-4-pyrone (ethyl maltol) are known for enhancing certain food flavors when present in optimally small amounts. U.S. Pat. No. 3,156,569 discloses the use of maltol as a flavor enhancer in combination with glutamate salts. U.S. Pat. No. 3,271,167 discloses artificial beef flavored gravy and broth compositions comprising alpha ketoglutarate, inosinate, glutamate and maltol. U.S. Pat. No. 3,293,045 discloses the use of maltol to enhance flavorings imparted by methyl salicylate, anethole and cinnamaldehyde. U.S. Pat. No. 3,296,079 discloses the use of maltol to mask the aftertaste of artificial sweeteners. Up to 400 parts per million of maltol in the final sweetened product may be used, but in larger amounts, maltol contributes a flavor note of its own. Optimally, lower concentrations of maltol are recommended. The maximum amount may be employed if bitter ingredients, for example stannous fluoride, are to be masked by the sweetening agent. U.S. Pat. No. 3,338,718 discloses that the addition of maltol in animal feeds up to 200 grams per ton to feed improves the rate of weight gain. U.S. Pat. No. 3,376,317 and 3,446,629 disclose that ethyl maltol is about six times as effective a flavor enhancer as maltol itself. Ethyl maltol is useful as a flavor enhancer in the range from one to 100 parts per million of the final food product. At higher concentrations, the food product begins to have an aroma contributed by the ethyl maltol itself. Ethyl maltol is disclosed to have an inherent flavor, not otherwise described, except that in sweet foods it creates a velvet mouth sensation.
Maltol has been identified by Saguma, H., et al., Agric. Biol. Chem. 42, 359 (1978) as a component of the mixture resulting from cellulose pyrolysis. The compound was said to be responsible for a pleasant caramel or burnt sugar-like aroma. Shigematsu, H., Agric. Biol. Chem. 35, 1751 (1971) and Shumacher, J. N., et al., J. Agric. Food Chem. 1977, 310, identified maltol in the water-soluble portion of cigarette smoke.
Maltol and ethyl maltol have been employed as additives for tobacco products and tobacco substitutes. U.S. Pat. No. 3,903,900, Wolt, et al., discloses the addition of up to 600 parts per million of maltol in a composition designed to enhance the flavor and aroma of tobacco. British Pat. No. 1,364,103 discloses an artificial smoking composition designed to replace tobacco. Such compositions may contain maltol or ethyl maltol up to 1.5% by weight, as a flavor and aroma imparting constituent.
Relative to the present invention, the concentrations of maltol or ethyl maltol in the ingested product are quite low; on the order of 1-400 ppm. An apparent exception is found in Belgian Pat. No. 840,306 by Grieske et al. Maltol was disclosed as a chelating agent useful for removing stains from teeth when applied topically to the teeth in a dentifrice, mouthwash or chewing gum at a concentration of up to 5% (50,000 ppm) for a maximum of one minute. Twice daily application was disclosed. Used as disclosed, such prior art compositions provide a maximum of 150 mg maltol per application assuming a 3 g stick of gum containing 5% maltol. Such use does not provide a minimally effective dose of maltol to be effective in the present invention, as described in detail infra. In fact, the topical application and short duration in the mouth indicate that substantially less than the calculated maximum dose of maltol would be ingested.
The value of maltol and ethyl maltol as food additives is greatly enhanced by their low toxicity. Maltol is included on the Flavor and Extracts Manufacturer's Association list of compounds generally recognized as safe for food additive purposes. Both compounds have been judged to be safe for an average daily intake of 1 mg per kg and 2 mg per kg for maltol and ethyl maltol, respectively. See Opdyke, D. L. J., Food Cosmet. Toxicol, 1975, 13, Suppl. 805 and 841. Consumption of as much as 1.5 grams per day of maltol appears to be completely harmless. Pharmacological studies have not been extensive. Both maltol and ethyl maltol are rapidly absorbed after oral administration and rapidly excreted, primarily as glucuronide and ethereal sulfate conjugates. In mice, maltol, 75 mg/kg, decreased spontaneous motor activity by approximately 50%. Ethyl maltol was also inhibitory, but somewhat less potent. Both compounds inhibited convulsions produced by pentylenetetrazole or strychnine while potentiating hexobarbital-induced sleeping time. See Aoyagi, N., Chem. Pharm, Bull. 221008 (1974). The dosage used in these experiments were 300 to 500 mg per kg, extremely high in view of the acute LD.sub.50 's of 820 and 910 mg per kg. for maltol and ethyl maltol respectively in mice. Oxygen intake by rat brain cortex slices in vitro was not affected by 1 maltol or ethyl maltol. These observations make it clear that maltol and ethyl maltol have pharmacological activity, although the nature of this activity is not clearly delineated at present.